Haloalkylthiodibenzothiepins

ABSTRACT

Novel aminoalkylthiodibenzothiepins and related compounds, physiologically tolerable acid addition salts thereof, a method of preparing same, pharmaceutical and veterinary preparations including same and methods of treating by administering same are disclosed. These compounds are useful as antidepressant, analgetic, and anticonvulsant agents.

This is a division of application Ser. No. 546,642, filed Oct. 28, 1983,issued as U.S. Pat. No. 4,668,695 on May 26, 1987, which is acontinuation of application Ser. No. 350,531, filed Feb. 24, 1982, nowabandoned, which is a continuation-in-part of application Ser. No.174,487, filed Aug. 1, 1980, now abandoned, which is continuation ofapplication Ser. No. 085,751, filed Oct. 17, 1979, now abandoned, whichis a continuation-in-part of application Ser. No. 860,082, filed Dec.13, 1977, now abandoned.

This invention relates to novel aminoalkylthiodibenzothiepins andrelated compounds and to their physiologically tolerable acid additionsalts which are useful as antidepressant, analgetic and anticonvulsantagents, to methods of treatment with pharmaceutically effective amountsthereof and to pharmaceutical and veterinary compositions containingsuch a compound as an essential active ingredient.

To the best of our knowledge, the compounds of this invention have notheretofore been described or suggested. Amethoclothepine of the formula##STR1## is reported to possess central depressant activity by M.Protvia, et al. II Farmaco XXI 98 (1966).

Japaneses Pat. No. 47-28998 entitled "A Method of ManufacturingTricyclic Compounds Having an Enolic Ether Bond" pertains to thepreparation of compounds depicted by the formula ##STR2## in which A isan alkylimino group, an oxy radical, a thio group or a sulfonyl group,R₁ is an alkylene group, R₂ and R₃ each represent an alkyl group or maybe bonded cyclically either through the alkylimine or not through thealkylimino group.

However, the compounds of the present invention possess significantdifferences with respect to the aforesaid prior art compounds and arenot suggested thereby. Furthermore, neither reference suggests theunique methodology required for the preparation of the compounds of thepresent invention.

The compounds of the present invention conform to the general formula##STR3## wherein X and Y are the same or different and each can behydrogen, halogen, trifluoromethyl, loweralkoxy, loweralkyl,loweralkylthio, loweralkylsulfonyl, loweralkylsulfinyl, amino, hydroxyor nitro; Z is halogen or ##STR4## R¹ is hydrogen, straight or branchedchain loweralkyl, cyano, cycloalkylloweralkyl wherein the cycloalkylring contains from 3 to 6 carbon atoms, phenoxycarbonyl of the formula##STR5## alkoxycarbonyl, loweralkenyl or loweralkynyl; R² is straight orbranched chain loweralkyl or cycloalkylloweralkyl wherein the cycloalkylring contains from 3 to 6 carbon atoms; and when R¹ and R² are takentogether with the nitrogen atom to which they are attached, the group R¹--N--R² forms a heterocycle which is morpholino, piperidino,pyrrolidinyl, or N-substituted piperazinyl in which the N-substituent isloweralkyl; m is the integer 0 or 1; and n is an integer of from 2 to 4;and a physiologically tolerable acid addition salt thereof.

In the above definitions, the term "lower" means a group containing upto 6 carbon atoms and the expression "alkylene glycol" refers to acompound formed by replacing 2 non-geminal hydrogen atoms of a straightor branched chain alkyl group of 2 or more carbon atoms by hydroxygroups.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric, and oxalic acids.

Compounds of the invention are prepared by one of several methods givenbelow. With the exceptions noted, X, Y, Z, R¹, R², m and n are asdefined earlier.

METHOD A

A 10,11-dihydro-10-hydroxydibenzo[b,f]thiepin, of the formula ##STR6##is reacted with aminoalkylthiol of the formula ##STR7## wherein R¹ andR² are the same or different and each can be a straight or branchedchain loweralkyl to produce a compound of the invention of the formula##STR8## This reaction is carried out with a catalyst/dehydrating agentof boron trifluoride etherate and in the presence of a suitable solventsuch as glacial acetic acid at a temperature of about ambient to reflux.

METHOD B

A 10,11-dihydro-10-oxydibenzo[b,f]thiepin, of the formula ##STR9## istreated in a manner similar to Method A to obtain a compound of theinvention of the formula ##STR10##

METHOD C

A compound prepared in Method A or B, wherein R¹ and R² are each methyland n is 2, can be treated with cyanogen halide such as cyanogen bromidein a suitable solvent and acid scavenger to obtain a mixture of onecompound of the invention of the formula ##STR11## and another compoundof the invention of the formula ##STR12## This reaction is carried outat a temperature of from about ambient to reflux. These two compounds ofthe invention may be isolated and collected by column chromatography.

METHOD D

A compound prepared in Method C of formula (a) can be reacted in a knownfashion with a suitable amine to obtain the corresponding compound ofthe invention of the formula ##STR13## wherein R¹ is hydrogen, straightor branched chain loweralkyl, cycloalkylloweralkyl, loweralkenyl orloweralkynyl; R² is straight or branched chain loweralkyl; and when R¹and R² are taken together with the nitrogen atom to which they areattached, the group R¹ --N--R² forms a heterocycle which isN-substituted piperazinyl, morpholino, piperidino or pyrrolidinyl. Apreferred method is carried out with a dimethylformamide solvent, anacid scavenger such as sodium bicarbonate and a reaction initiator suchas potassium iodide at a temperature of from ambient to the refluxtemperature of the reaction mixture.

METHOD E

A compound prepared in Method A or B can be treated with achloroformate, e.g. an alkyl or phenyl chloroformate, at a temperatureof from 25° to 125° C., in a solvent such as methylene chloride, tolueneor benzene to provide the corresponding compound of the invention inwhich Z is ##STR14## with R¹ being alkoxy or phenoxy carbonyl.

METHOD F

A compound prepared by Method E wherein X and Y are groups as hereinbefore-described other than fluoro is treated with a base such as sodiumor potassium hydroxide in a solvent such as water, ethanol or ethyleneglycol at a temperature of from ambient to reflux to provide thecorresponding compound of the invention in which R¹ is hydrogen and Xand Y are groups as herein before-described other than fluoro.

When a compound of the formula ##STR15## wherein X is hydrogen, bromo,chloro, iodo, trifluoromethyl, loweralkoxy, loweralkyl, loweralkanoyl,loweralkylthio, loweralkylsulfinyl, amino or nitro; R² is straight orbranched chain loweralkyl, loweralkenyl, loweralkynyl orcycloalkyloweralkyl wherein the cycloalkyl ring contains from 3 to 6carbon atoms; R³ is loweralkyl or phenyl; and n is an integer of from 2to 4 is treated with an alkali metal or alkaline earth metal hydroxidein an inert solvent in addition to cleavage of the alkoxy- orphenoxycarbonyl groups to the secondary amino function, displacement ofthe fluoro groups occurs to give a hydroxydibenzo[b,f]thiepin of theformula ##STR16## wherein R¹ is hydrogen and R², X and n are as definedabove.

The cleavage displacement reaction is conveniently performed in an inertsolvent such as an alkylene glycol having 2 to 6 carbon atoms. Suitablealkylene glycols include ethylene glycol, 1,2- and 1,3-propylene glycol,1,4-, 1,3-, 1,2- and 2,3-butylene glycol, 1,4-, 1,5- and 2,4-pentyleneglycol, 1,5-, 1,6- and 2,5-hexylene glycol and the like. Ethylene glycolis preferred.

While the cleavage displacement reaction temperature is not narrowlycritical, it is desirable to carry out the reaction at a temperature offrom about 100° to 200° C. to assure a reasonable rate of both cleavageand displacement. A reaction temperature of about 160° C. is preferred.

As suitable alkali metal and alkaline earth hydroxides there may bementioned lithium, sodium and potassium and calcium and bariumhydroxides, respectively. Alkali metal hydroxides are preferred,potassium hydroxide being most preferred.

The cleavage displacement reaction is particularly applicable for thepreparation of hydroxydibenzo[b,f]thiepins wherein X is hydrogen, R² isloweralkyl and n is 2. The reaction is most particularly applicable forthe preparation of hydroxydibenzo[b,f]thiepins wherein R² is methyl andthe hydroxy group is attached to the 2-position of the nucleus startingfrom fluorodibenzo[b,f]thiepines wherein R² is methyl and the fluorogroup is attached to the 2-position of the ring system.

METHOD G

A compound prepared in Method F is treated with a straight or branchedchain loweralkyl halide, loweralkynyl halide or cycloalkylloweralkylhalide under conditions normal for such reactions to provide thecorresponding compound of the invention in which R¹ is straight orbranched chain loweralkyl, loweralkenyl, loweralkynyl orcycloalkylloweralkyl. A preferred method is to carry out thissubstitution in the presence of a solvent such as dimethylformamide, anacid scavenger such as sodium bicarbonate and a reaction initiator suchas potassium iodide at the reflux temperature of the solvent.

METHOD H

A compound prepared in any of the above methods, which includes a nitrogroup can be reduced by a conventional method to produce thecorresponding amino compound.

As is appreciated by those skilled in the art, specific reactionconditions in any of the above methods are dependent on and are afunction of the ingredients of each procedure.

The compounds of the invention are useful in the treatment of depressionin mammals which is evidenced by their ability to inhibittetrabenazine-induced ptosis in mice [International Journal ofNeuropharmacology 8, 73 (1969)], a standard assay for usefulantidepressant properties.

Compounds of the invention are further useful as analgesic agents due totheir ability to alleviate pain in mammals which is demonstrated in thephenyl-p-quinone writhing assay in mice, a standard assay for analgesia[Proc. Soc. Exptl. Biol. Med., 95, 729 (1957)].

Compounds of the present invention are still further useful asanticonvulsant agents for mammals, as evidenced by the method ofWoodbury, L. A. and Davenport, V. D. in Arch. Int. Pharmacodynam, Vol.92, (1952) at pages 97-107.

These compounds are useful, as any of the above three categories ofpharmaceutical agents, when administered in an amount ranging from about0.1 to 100 mg per kg of body weight per day.

Compounds of the present invention are essentially devoid of centralnervous system depressant (neuroleptic) activity as determined in theapomorphine induced climbing mice assay; a standard test for centralnervous system depressant (neuroleptic) activity described in Example20.

Compounds of the present invention exhibit a combination ofantidepressant activity as determined in the hereinbeforedescribedinhibition of tetrabenazine induced ptosis in mice and analgesicactivity as determined in the hereinbeforedescribed phenyl-p-quinonewrithing assay in mice and the modified D'Amour-Smith analgesia (tailflick) assay, a standard test for analgesic activity described inExample 21.

Examples of compounds of the invention include:

11-[γ-(dimethylamino)propylthio]-2-ethylsulfonyldibenzo[b,f]thiepin;

11-[β-(bromo)ethylthio]-2-methoxy-10,11-dihydrodibenzo[b,f]thiepin;

2-ethyl-11-[β-(methylamino)ethylthio]dibenzo[b,f]thiepin;

11-[β-(ethylmethylamino)ethylthio]-2-methylsulfinyldibenzo[b,f]thiepin;

11-[β-(ethylmethylamino)ethylthio]-2-methylthiodibenzo[b,f]thiepin;

10,11-dihydro-10-[β-(piperidino)ethylthio]dibenzo[b,f]thiepin;

10,11-dihydro-10-[γ-(N-methylpiperazino)propylthio]dibenzo[b,f]thiepin;

10,11-dihydro-10-[γ-(piperidino)-n-butylthio]dibenzo[b,f]thiepin;

10-[β-(pyrrolidino)ethylthio]dibenzo[b,f]thiepin;

3-chloro-11-[β-(ethylmethylamino)ethylthio]dibenzo[b,f]thiepin;

11-[β-(ethylamino)ethylthio]-10,11-dihydro-4-nitrodibenzo[b,f]thiepin;

11-[β-(ethylamino)ethylthio]-3-trifluoromethyldibenzo[b,f]thiepin;

2-amino-11-[β-(ethylamino)ethylthio]dibenzo[b,f]thiepin;

11-[β-(ethylamino)ethylthio]-3-methoxydibenzo[b,f]thiepin;

11-[β-(diethylamino)ethylthio]-2-n-propyldibenzo[b,f]thiepin;

11-[β-(methylamino)ethylthio]-3-methylthiodibenzo[b,f]thiepin;

8-chloro-10,11-dihydro-10-[β-(dimethylamino)ethylthio]-2-methyldibenzo[b,f]thiepin;

3-fluoro-11-[β-(methylamino)ethylthio]dibenzo[b,f]thiepin;

2-bromo-7-fluoro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin;

3-ethyl-11-[β-(methylamino)ethylthio]dibenzo[b,f]thiepin;

11-[β-(ethylamino)ethylthio]-4-nitrodibenzo[b,f]thiepin;

2-methyl-11-[β-(N-methyl-N-methoxycarbonylamino)ethylthio]dibenzo[b,f]thiepin;

10-[β-(cyclopropylmethyl-N-methylamino)ethylthio]dibenzo[b,f]thiepin;

10-[β-(N-allyl-N-methylamino)ethylthio]dibenzo[b,f]thiepin; and

10-[β-(N-methyl-N-propargylamino)ethylthio]dibenzo[b,f]thiepin.

Effective quantities of the compounds of the invention may beadministered to a patient by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable addition salts for purposes of stability,convenience of crystallization, increased solubility and the like.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed as tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions in such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied to between 0.5% and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampuls, disposable syringes or multiple dose vialsmade of glass or plastic.

EXAMPLE 1

Boron trifluoride etherate is added to a solution of 20.0 g of2-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin, 21.8 g ofβ-dimethylaminoethanethiol hydrochloride and 218 ml of glacial aceticacid. After total addition the reaction mixture is stirred for 30minutes and then permitted to stand for 48 hours. Thereafter, themixture is poured into 1200 ml of a 10% sodium hydroxide solution andthe basified mixture is extracted with methylene chloride. The combinedmethylene chloride fractions are successively washed with water, driedand filtered and the filtrate evaporated to dryness leaving a red oil.The oil is column chromatographed through a silica gel/methylenechloride column with a 2-4% methanol in methylene chloride mixture asthe element. The purified product is converted to its hydrogen chloridesalt of 2-chloro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepinhydrochloride.

Analysis: Calculated for C₁₈ H₁₈ ClNS₂.HCl: 56.24%C; 4.98%H; 3.64%N.Found: 56.35%C; 5.17%H; 3.47%N.

EXAMPLE 2

A sample of 10,11-dihydro-10-oxodibenzo[b,f]thiepin is treated accordingto the manipulative procedure of Example 1 to provide10-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin hydrochloride.

EXAMPLE 3

To a mixture of 1.08 g of β-dimethylaminoethanethiol hydrochloride and2.5 ml of boron trifluoride etherate is added dropwise a mixture of 1.0g of 2-chloro-10,11-dihydro-11-hydroxyspirodibenzo[b,f]thiepin in 8 mlof glacial acetic acid. After total addition, the reaction mixture isstirred at ambient temperature for 30 minutes and then permitted tostand for 24 hours. Thereafter, the reaction is poured into 50 ml of asaturated potassium carbonate-ice solution where it is extracted withether. The combined ether extracts are, successively, washed with adilute potassium carbonate solution and water and dried, filtered andevaporated. The resulting oil is chromatographed through a silicagel/methylene chloride, a 5% methyl alcohol in methylene chloride eluantand then converted to the maleic acid salt, mp, 99°-101° C. of2-chloro-10,11-dihydro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepinmaleate.

Analysis: Calculated for C₁₈ H₂₀ ClNS₂.C₄ H₄ O₄ : 56.70%C; 5.19%H;3.01%N. Found: 56.70%C; 5.29%H; 3.03%N.

EXAMPLE 4

A sample of 10-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin, freebase of Example 3, is treated according to the manipulative procedure ofExample 3 to provide10,11-dihydro-10-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepinhydrochloride.

EXAMPLE 5

A solution of 1.0 g of2-chloro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin free base ofExample 1, in 10 ml of methylene chloride is added dropwise to astirring solution of 0.5 g of cyanogen bromide and 1.0 g of potassiumcarbonate in 7 ml of methylene chloride. After total addition, thereaction is permitted to stand with complete reaction occuring afterabout four hours. After the reaction is completed the mixture isfiltered and the filtrate evaporated leaving an oil. The oil ischromatographed through a silica gel/methylene chloride column withmethylene chloride as the eluant. The desired fraction is evaporated todryness leaving2-chloro-11-[β-(N-cyano-N-methyl)aminoethylthio]dibenzo[b,f]thiepin as ayellow oil.

Analysis: Calculated for C₁₈ H₁₅ ClN₂ S₂ : 60.23%C; 4.21%H; 7.81%N.Found: 60.62%C; 4.19%H; 7.75%N.

EXAMPLE 6

To a stirring solution of 0.50 g of phenyl chloroformate and 0.2 g ofsodium bicarbonate in 20 ml of methylene chloride is added dropwise asolution of 0.95 g of2-chloro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin, free baseof Example 1, in 10 ml of methylene chloride. After total addition thereaction is successively stirred at 25° C. for 24 hours, filtered,diluted with 25 ml of methylene chloride, washed with a 10% sodiumhydroxide solution, washed with water, dried and filtered. The filtrateis evaporated leaving a yellow oil which is chromatographed through asilica gel/methylene chloride column with methylene chloride as theeluant. The purified product is the yellow oil of2-chloro-11-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenzo[b,f]thiepin.

Analysis: Calculated for C₂₄ H₂₀ ClNO₂ S₂ : 63.49%C; 4.44%H; 3.09%N.Found: 63.76%C; 4.49%H; 2.90%N.

In a similar fashion a sample of10-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin, free base of Example2, is treated to provide10-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenzo[b,f]thiepin and11-[β-(dimethylamino)ethylthio]-2-fluorodibenzo[b,f]thiepin, free baseof Example 15, is treated to provide2-fluoro-11-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenzo[b,f]thiepin.

EXAMPLE 7

A solution of 5.6 g of2-chloro-11-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenzo[b,f]thiepin,Example 6, 127 ml of ethylene glycol and 10.8 g of potassium hydroxideis stirred at 150°-155° C. for 30 minutes. Thereafter the reactionmixture is poured onto 300 ml of ice-water and the aqueous mixture isextracted with an ether-toluene (1:1) mixture. The combined extracts,successively, are washed well with water, dried and filtered and thefiltrate evaporated leaving an orange oil. The oil is converted to itshydrogen chloride acid salt which is recrystallized from amethanol-acetone-ether mixture to give the product, mp 194°-196° C. of2-chloro-11-[β-(methylamino)ethylthio]dibenzo[b,f]thiepin hydrochloride.

Analysis: Calculated for C₁₇ H₁₆ ClNS₂.HCl: 55.13%C; 4.63%H; 3.78%N.Found: 55.28%C; 4.71%H; 3.93%N.

In a similar fashion,10-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio]dibenzo[b,f]thiepin,hereinabove described, is treated to provide10-[β-(methylamino)ethylthio]dibenzo[b,f]thiepin hydrochloride.

EXAMPLE 8

A solution of2-chloro-10,11-dihydro-11-[β-dimethylamino)ethylthio]dibenzo[b,f]thiepin,free base of Example 3, in 10 ml of chloroform is added dropwise to asolution of a stoichiometric amount of cyanogen bromide and an excessamount of potassium carbonate in 5 ml of chloroform. After totaladdition the reaction mixture is permitted to stand for 10 minutes andthen filtered. The filtrate is concentrated to dryness leaving theproduct 11-(β-bromoethylthio)-2-chloro-10,11-dihydrodibenzo[b,f]thiepin.

In a similar fashion,11-[β-(dimethylamino)ethylthio]-2-fluorodibenzo[b,f]thiepin, free baseof Example 15, is treated to provide11-(B-bromoethylthio)-2-fluorodibenzo[b,f]thiepin.

EXAMPLE 9

A mixture of stoichiometric amounts of2-chloro-11-(β-bromoethylthio)-10,11-dihydrodibenzo[b,f]thiepin, Example8, and N-methylpiperzine, an excess amount of sodium bicarbonate, and1.0 g of potassium iodide in 15 ml of dimethylformamide is stirred at80° C. for 16 hours. The mixture is permitted to cool before beingdiluted with water. The biphasic mixture is extracted thrice with 100 mlportions of ether, the ether extracts are combined and shaken vigorouslywith a large excess of 2N hydrochloric acid. The acidic solution isbasified, liberating the free amine which is extracted into benzene. Thebenzene solution is dried and the benzene removed under vacuum, leavingthe product2-chloro-10,11-dihydro-11[β-(4-methylpiperazinyl-1-yl)ethylthio]dibenzo[b,f]thiepin.

In a similar fashion, substituting morpholine for N-methylpiperazineprovides2-chloro-10,11-dihydro-11-(β-morpholinoethylthio)dibenzo[b,f]thiepin.

EXAMPLES 10 & 11

By following the manipulative procedure of Example 2, respectivelysubstituting β-diisopropylaminoethanethiol hydrochloride,β-diethylaminoethanethiol hydrochloride for β-dimethylaminoethanethiolhydrochloride provides Example 10,10-[β-(diisopropylamino)ethylthio]dibenzo[b,f]thiepin hydrochloride andExample 11, 10-[β-(diethylamino)ethylthio]dibenzo[b,f]thiepinhydrochloride.

EXAMPLE 12

a. A solution of stoichiometric amounts of2-(4-methylsulfonylphenylthio)benzyl nitrile and 85% potassium hydroxidein an alcohol-water mixture is stirred at 115° C. for 24 hours.Thereafter the reaction mixture is concentrated to an oil. The oil isdissolved in water and the aqueous solution is successively, washed withether, acidified with dilute hydrochloric acid again providing an oil.This oil is dissolved in methylene chloride and the solution,successively, is dried, filtered and concentrated to dryness leaving theproduct 2-(4-methylsulfonylphenylthio)phenylacetic acid.

b. A mixture of 1.0 g of 2-(4-methylsulfonylphenylthio)phenylacetic acidand 10 ml of polyphosphoric acid under nitrogen is stirred at 90°-100°C. for 2 hours. The reaction mixture is permitted to cool and thenpoured into 100 ml of an ice-water slurry. The aqueous solution isbasified with 20% sodium hydroxide before being extracted with methylenechloride. The combined extracts are dried and then evaporated to drynessleaving an oil. The oil is chromatographed through a silica gel columnwith a 2% methanol in methylene chloride eluant. The chromatographedsolution is evaporated to dryness providing10,11-dihydro-2-methylsulfonyl-11-oxodibenzo[b,f]thiepin.

c. A solution of stoichiometric amounts of10,11-dihydro-2-methylsulfonyl-11-oxodibenzo[b,f]thiepin anddimethylaminoethanethiol hydrochloride and 15 ml of boron trifluorideetherate in 37 ml of glacial acetic acid is stirred until reaction iscompleted. Thereafter the reaction mixture is poured into 300 ml of acold sodium hydroxide solution and the resulting solution is extractedwith methylene chloride. The combined extracts are washed with water anddried before being filtered. The filtrate is evaporated to drynessleaving an oil which is chromatographed through a silica gel/methylenechloride column with methanol (2-4%) in methylene chloride eluant. Thechromatographed solution is evaporated to dryness leaving11-[(β-dimethylamino)ethylthio]-2-methylsulfonyldibenzo[b,f]thiepin.

EXAMPLE 13

A solution of 2.0 g of11-(β-bromoethylthio)-2-chloro-10,11-dihydrodibenzo[b,f]thiepin, 1.2 gof potassium iodide and 20 ml of anhydrous dimethylformamide is stirredat 25° C. while methylamine is bubbled in over five minutes. Thereaction is stirred at 25° C. for 24 hours, poured into 100 ml of icewater and the resulting product extracted with ether. The etherfractions are combined, washed with water and dried over magnesiumsulfate. The dried solution is filtered and evaporated to an oil.Treatment of the oil with ethereal maleic acid provides2-chloro-10,11-dihydro-11-[β-(methylamino)ethylthio]dibenzo[b,f]thiepinmaleate, mp 110°-112° C. A sample is recrystallized from acetone-etherfor elemental analysis:

Calculated for C₁₇ H₁₈ ClNS₂.C₄ H₄ O₄ : 55.80%C; 4.91%H; 3.10%N. Found:55.91%C; 4.86%H; 2.88% N.

In a similar fashion, 11-(β-bromoethylthio)-2-fluorodibenzo[b,f]thiepinof Example 8 is treated to provide11-[β-(methylamino)ethylthio]-2-fluorodibenzo[b,f]thiepin.

EXAMPLE 14

To a solution of 6.8 g of β-dimethylaminoethanethiol hydrochloride and45 ml of glacial acetic acid, 16 ml of boron trifluoride etherate isadded at room temperature with stirring. To the solution is addeddropwise 6.0 g of10,11-dihydro-2-fluoro-11-hydroxyspirodibenzo[b,f]thiepin, dissolved in50 ml of glacial acetic acid and the reaction mixture is stirred at roomtemperature for 6 hours and allowed to stand at room temperature for 96hours. The reaction mixture is poured onto a mixture of 300 ml ofsaturated potassium carbonate solution and 300 ml of ice. The basicsolution is extracted with ether and the ether fractions are combined,washed with dilute potassium carbonate solution, water and dried overanhydrous magnesium sulfate. The solution is filtered, evaporated andthe residue chromatographed on a silica gel dichloromethane column with5-15% methanol/dichloromethane being used for elution to give2-fluoro-10,11-dihydro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepinhydrochloride.

Analysis: Calculated for C₁₈ H₂₀ FNS₂.HCl: 58.43%C; 5.72%H; 3.79%N.Found: 58.31%C; 5.73%H; 3.80%N.

EXAMPLE 15

To a solution of 5.0 g of10,11-dihydro-2-fluoro-11-oxodibenzo[b,f]thiepin in 52 ml of glacialacetic acid is added 5.81 g of β-dimethylaminoethanethiol hydrochloride.After the addition is complete, the mixture is heated to 90° C.whereuponit becomes homogenous. The solution is cooled to 25° C. and15.4 ml of boron trifluoride etherate is added. After stirring for 3days at 25° C., an additional 8 ml of boron trifluoride etherate isadded and the solution is heated at 60° C. for 5 hours. The reactionmixture is poured into 150 ml of 20% sodium hydroxide solution at 0° C.The mixture is extracted with ether and the combined extracts are washedwith 20% sodium hydroxide solution, water, saturated sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered.Chromatography of the filtrate on silica gel with 5%methanol/dichloromethane elution provides2-fluoro-11-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin which isconverted to its hydrochloride, mp 209°-211° C.

Analysis: Calculated for C₁₈ H₁₈ FNS₂.HCl: 58.76%C; 5.20%H; 3.81%N.Found: 58.57%C; 5.09%H; 3.53%N.

EXAMPLE 16

Into a mixture of 200 mg of potassium iodide and 35 ml of drydimethylformamide is bubbled monomethylamine at a fast rate for 5minutes. A solution of 4.34 g of11-(β-bromoethyl)-10,11-dihydro-2-fluorodibenzo[b,f]thiepin in 15 ml ofdry dimethylformamide is added over 7 minutes while methylamine isbubbled in. Stirring with vigorous bubbling of methylamine is continuedfor an additional 38 minutes. The reaction is then stoppered and stirredfor 3.25 hours. The solution is poured into 350 ml of chilled water andextracted with three 100 ml-portions of ether. The combined etherextract is washed with five 75 ml-portions of water and one 35ml-portion of saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered and evaporated to give 3.60 g of an oil. Theoil is dissolved in ether and treated with ethereal maleic acid. Tworecrystallizations from acetone-ether give2-fluoro-10,11-dihydro-11-[(β-methylaminoethyl)ethyl)thio]dibenzo[b,f]thiepinmaleate, mp 114°-116° C.

Analysis: Calculated for C₁₇ H₁₈ FNS₂ : 57.93% C; 5.09%H; 3.22%N. Found:57.62%C; 5.06%H; 3.09%N.

EXAMPLE 17

A mixture of 7.0 g of2-fluoro-11-[β-(N-methyl-N-phenoxycarbonylamino)ethylthio[b,f]thiepin,40 g of 85% potassium hydroxide and 150 ml of ethylene glycol is stirredat 160°-170° C. for 2 hours. The cooled mixture is diluted with 300 mlof ice-water and the aqueous solution is acidified with concentratedhydrochloric acid. Basification with ammonium hydroxide (pH 9˜10) givesa solid which is collected, air-dried and recrystallized from acetoneand acetone-hexane to give2-hydroxy-11-[β-(methylamino)ethylthio]dibenzo[b,f]thiepin, mp 147°-149°C.

Analysis: Calculated for C₁₇ H₁₇ NOS₂ : 64.72%C; 5.43%H; 4.44%N. Found:64.74%C; 5.59%H; 4.36%N.

EXAMPLE 18

A solution of 4.62 g of cyanogen bromide in 50 ml of chloroform wasadded dropwise to a solution of 11.5 g of10,11-dihydro-10-[β-(dimethylamino)ethylthio]dibenzo[b,f]thiepin in 50ml of chloroform, with stirring. After stirring at room temperature for10 min, the solution was evaporated under reduced pressure, and the oilyresidue was chromatographed over a column of silica gel. Elution withdichloromethane gave 10.8 g (84%) of10,11-dihydro-10-[β-(bromoethyl)thio]dibenzo[b,f]thiepin, mp 60°-62° C.

Analysis: Calculated for C₁₆ H₁₅ BrS₂ : 54.70%C; 4.30%H. Found: 54.89%C;4.24%H.

EXAMPLE 19

Into a solution of10,11-dihydro-10-[β-bromoethyl)thio]dibenzo[b,f]thiepin in 10 ml ofanhydrous dimethylformamide containing a few crystals of potassiumiodide was bubbled gaseous monomethylamine for 30 min. The saturatedsolution was stoppered and allowed to stand at room temperature for 16hrs. The mixture was diluted with water. The organic materials wereextracted into ether and the combined ether solution was washed fourtimes with water. After drying, the ethereal solution was treated withanhydrous hydrochloric acid to give a precipitate. Trituration withmethanol gave 2.2 g (65.3%) of10,11-dihydro-10-[β-(methylamino)ethylthio]dibenzo[b,f]thiepinhydrochloride, mp 117√-119° C.

Analysis: Calculated for C₁₇ H₁₉ NS₂.HCl: 60.42%C; 5.97%H; 4.15%N.Found: 60.20%C; 5.91%H; 4.15%N.

EXAMPLE 20 Central Nervous System Depressant (Neuroleptic) ActivityClimbing Mice Assay

Method:

The subject CD-1 male mice (23-27 grams) were group-housed understandard laboratory conditions. The mice were individually placed inwire mesh stick cages (4"×4"×10") and were allowed one hour foradaptation and exploration of the new environment. Then apomorphine wasinjected subcutaneously at 1.5 mg/kg, a dose causing climbing in allsubjects in 30 minutes. Compounds to be tested for neuroleptic activitywere injected intraperitoneally 30 minutes prior to the apomorphinechallenge at a screening dose of 10 mg/kg.

For evaluation of climbing, 3 readings were taken at 10, 20 and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior    Score                                                    ______________________________________                                        Mice with:                                                                    4 paws on bottom (no climbing)                                                                     0                                                        2 paws on the wall (rearing)                                                                       1                                                        4 paws on the wall (full climb)                                                                    2                                                        ______________________________________                                    

Mice consistently climbing before the injection of apomorphine werediscarded.

With full-developed apomorphine climbing, the animals were hanging ontothe cage walls, rather motionless, over longer periods of time. Bycontrast, climbs due to mere motor stimulation usually only lasted a fewseconds.

The climbing scores were individually totaled (maximal score: 6 permouse over 3 readings) and the total score of the control group (vehicleintraperitoneally-apomorphine subcutaneously) was set to 100%. ED₅₀values with 95% confidence limits were calculated by a Linear RegressionAnalysis.

Results:

    ______________________________________                                                        Dose     Activity                                             Compound        (mg/kg)  (% Climbing Score)                                   ______________________________________                                        2-chloro-11-[β-(dimethyl-                                                                10       -5                                                   amino)ethylthio]dibenz                                                        [b,f]thiepin                                                                  10-[β-(dimethylamino)-                                                                   10       +5                                                   ethylthio]dibenz[b,f]                                                         thiepin                                                                       ______________________________________                                    

References:

Protais, P., Costentin, J. and Schwartz, J: Climbing behavior induced byapomorphine in mice: A simple test for the study of dopamine receptorsin striatum. Psychopharmacol., 50: 1-6, 1976.

Costall, B., Naylor, R. J. and Nohria, V.: Climbing behavior induced byapomorphine in mice: A potent model for the direction of neurolepticactivity. Eur. J. Pharmacol., 50: 39-50, 1978.

EXAMPLE 21 Analgesic Activity Modified D'Amour-Smith Assay (Tail Flick)

Method:

Male mice (Charles River: CD-1) from 18-30 grams were used as testsubjects. The mouse tails were individually placed on a "Vee" block and,subsequently, a painful stimulus was produced by an intense light beam(Emdie Instrument Co., Louisa, VA). The subject quickly responds to thenoxious stimuli by flicking its tail. The reaction time, the intervalbetween stimulus onset and response, was automatically measured in1/10-second increments. Prior to drug administration, two controlreadings of reaction time were measured for each subject withapproximately 15 minutes separating the tests. Subjects were discardedif their reaction times in these control tests varied by more than onesecond or if their inclusion in the study group caused the spread ofreaction times to exceed three seconds.

The mean response time (x) and the standard deviation (SD) of the valueswere then calculated for each set of control scores. The formulapresented below was used to calculate cut-off values (C.O.) for each setof control scores and the average of these C.O. values was used todetermine evidence of analgesic activity in subsequent drug testing.

    x+SD(2)=C.O.

x=Mean control response times for group

SD=Standard deviation of the response times

The C.O. value was actually a determination of a reaction time whichexceeds the mean by two standard deviations. Any reaction time, insubsequent drug tests, which was greater than the C.O. value, thereforeexceeds 95% of a normal Gaussian distribution and was called a "positiveresponse" indicative of analgesic activity. Latency changes werecalculated by substracting the tail flick latency of the average controltimes from the latency after treatment for each mouse.

Compounds were tested in treatment groups of ten subjects and drugs,prepared in distilled water, were generally administered subcutaneously(s.c.) in volumes equivalent to 10 cc/kg. The initial testing wasusually in the form of a time response at intervals of 15, 30, 45 and 60minutes after dosing. If analgesic activity was still increasing at 60minutes, then two additional groups were tested at 90 minute and 120minute post dosing.

A time response indicated the period of greatest analgesic effect afterdosing. Percent analgesic activity was calculated in the followingmanner: ##EQU1##

The ED₅₀ was determined at the peak time of drug activity. A minimum ofthree dose groups were employed. Drugs were administered in a randomizedmanner. ED₅₀ 's were calculated using Litchfield-Wilcoxon (LITWL on PDPII) computer analysis.

Grp.=Group

Veh.=Vehicle

Results:

    ______________________________________                                                          Dose     Analgesic Activity                                 Compound          (mg/kg)  (%)                                                ______________________________________                                        10-[β-dimethylamino)-                                                                      25       20                                                 ethylthio]dibenz[b,f]thiepin                                                  2-chloro-11-[β-(dimethylamino)                                                             14.3     50                                                 ethylthio]dibenz[b,f]thiepin                                                  ______________________________________                                    

Reference:

(1) D'Armour, Fred and Smith, Donn. J. Pharmacol. Exptl. Therap. 72:74-79 (1941).

What is claimed is:
 1. A compound of the formula ##STR17## wherein X andY are the same or different and each can be hydrogen, halogen,trifluoromethyl, loweralkoxy, loweralkyl, loweralkanoyl, loweralkylthio,loweralkylsulfonyl, loweralkylsulfinyl, amino, hydroxy or nitro; Z ishalogen; and n is an integer of from 2 to 4; or a physiologicallytolerable acid addition salt thereof.
 2. The compound defined in claim 1which is 11-(β-bromoethylthio)-2-chloro-10,11-dihydrodibenzo[b,f]thiepinor a physiologically tolerable acid addition salt thereof.
 3. Thecompound as defined in claim 1 which is11-[β-(bromoethyl)thio]-2-methoxy-10,11-dihydrodibenzo[b,f]thiepin or aphysiologically tolerable acid addition salt thereof.
 4. The compound asdefined in claim 1 which is10,11-dihydro-10-[β-(bromoethyl)thio]dibenzo[b,f]thiepin, or aphysiologically tolerable acid addition salt thereof.
 5. Apharmaceutical composition for treating pain, depression or convulsionswhich comprises between 0.5 and about 70% by weight of a compounddefined in claim 1 and a pharmaceutically acceptable carrier therefor.6. A method of treating depression which comprises administering to apatient suffering from depression a pharmaceutically effective amount ofa compound defined in claim
 1. 7. A method of treating pain whichcomprises administering to a patient in pain a pharmaceuticallyeffective amount of a compound defined in claim
 1. 8. A method oftreating convulsions which comprises administering to a patientsusceptible to convulsions a pharmaceutically effective amount of acompound defined in claim 1.